The present invention provides a new compound, which we have termed Leustroducsin H, and which has the formula (I) shown hereafter. The invention also provides a method for the preparation of this compound, as well as compositions and methods of therapy using this compound.
The compound of the present invention is a novel compound which stimulates the production of blood platelets and hence is useful in the treatment of thrombocytopenia. Thrombocytopenia may be induced by various causes, such as immune abnormality or adverse reactions after cancer chemotherapy or radiotherapy. It is a severe disease which, if aggravated, causes bleeding throughout the body and sometimes results in death. At present, the only sure way to treat thrombocytopenia is by symptomatic therapy involving blood platelet transfusion.
Various types of cytokine are known, which compounds have a hematopoietic activity. These include certain interleukins, for example interleukin 6 (hereinafter abbreviated to IL-6), interleukin 11 (hereinafter abbreviated to IL-11) and leukemia inhibitory factor (hereinafter abbreviated to LIF). Amongst other activities, these compounds are known to stimulate the production of blood platelets and, as such, are expected to be clinically useful [Ishibashi et al., Blood 74, 1241-1244 (1989); Asano et al., Blood 75, 1602-1605 (1990); Okada et al., Blood Tumor 22, 23-31 (1991)].
It has been found that the administration of these compounds themselves to humans by various routes results in clear pharmacological effects, which leads to the possible use of these compounds in therapy. However, it is thought that these compounds are essentially produced in vivo by certain kinds of cell (e.g. lymphocytes, monocytes, fibroblasts, vascular endothelial cells and stromal cells) through a complicated regulatory system, and that they play homeostatic roles in the production of various kinds of blood cell. Accordingly, if these compounds are administered without any consideration for the delicate balance of this regulatory mechanism, several side effects may be observed, which may be caused by the imbalance of this regulatory mechanism; examples of such side effects include hepatic tissue damage, weight loss, fever and rigor.
It is also known that various kinds of low-molecular weight immunoactivators, such as muramyldipeptides (hereinafter abbreviated to MDP) are capable of increasing the total number of blood platelets [R. Nakajima et al., Arzneimittel-Forsch./Drug Research 41, 60-65 (1989)]. It is thought that these compounds stimulate production of IL-6 indirectly via the activation of monocytes and macrophages. The IL-6 produced then causes an increase in the number of thrombocytes. However, it is also known that other, perhaps less desirable, physiological effects based on the activation of macrophages, for example, formation of monokines, such as interleukin 1 (IL-1) and tumor necrosis factor (TNF), occur at the same time. Adverse reactions, such as fewer, are also observed [Jap. J. Radiotherapy 48 (4), 514 (1988)].
It is apparent, therefore, that there remains a need for an agent which is capable of stimulating blood platelet formation and which can therefore be used in the treatment of thrombocytopenia, but which agent does not cause an imbalance in any internal regulatory mechanism or result in adverse effects, such as those described above.
European Patent Publication No. 506,463 discloses certain new pyranone derivatives, named as Leustroducsin A, B and C, which have the following formula: ##STR2## in which R represents a 5-methylhexanoyl group, a 6-methyloctanoyl group or a 7-methyloctanoyl group respectively. These compounds, which were isolated from a strain of the micro-organism Streptomyces platensis, are disclosed to have activity in: reduction of adverse reactions resulting from cancer chemotherapy or radiotherapy, protection against infections, activation of macrophages, improvement of cerebral function as well as activity as antifuneral agents.
Japanese Patent Publication No. Hei 5-213758, which was published on 24th Aug. 1993, describes the use of Leustroducins A, B and C in the treatment of thrombocytopoiesis.
European Patent Publication No. 329 361 discloses certain new 2-pyranone derivatives which resemble the compound of the present invention, except that they are substituted in a manner similar to the substitution in the compounds of European Patent Publication No. 506 463, above. These prior art compounds are, furthermore, only said to be agricultural biocides and are not shown in the published art to have the valuable and unexpected therapeutic and prophylactic activities of the compound of the present invention.
Further compounds, very similar to those described in European Patent Publication No. 329 361 and having essentially the same utility, are described in Japanese Patent Application Kokai Hei 2-186.
The Journal of Antibiotics, 42 (1989) 1331-1343 discloses a novel antitumor compound, which the authors call "Phospholine" and which is produced by a micro-organism of the genus Streptomyces. This compound, like that of the present invention, has both an amino group and a phosphoric acid group, but has a different molecular formula. The compound is, therefore, clearly distinguished from that of the present invention.